Background: In labor analgesia, epidurals are the gold standard. However, inadequate analgesia in laboring patients with lumbar epidurals is between 1.7-19.8% [1]. Catheter tip location determines which region of the body is anesthetized. During early labor, epidural catheter placement near lumbar nerve roots provides excellent analgesic coverage while catheter placement near sacral nerve roots can lead to inadequate analgesia [2]. While commonly used to predict thoracic epidural placement, the noninvasive epidural stimulation test (EST) has not been tested for predicting lumbar versus sacral epidural placement [3]. In EST, muscle twitching indicates lumbar or sacral nerve root proximity. This study examines EST's ability to predict lumbar versus sacral epidural placement and its labor analgesia quality.

Methods: A single-center, observational study was performed after approval by Stanford University’s Institutional Review Board (reference ID 52856) and submission to the National Clinical Trials Registry (NCT 04109365). After obtaining consent, patients rated their pain on a 0-10 scale (0 = no pain) immediately preceding epidural catheter placement during stage 1 of labor. After epidural catheter placement, EST was performed. The twitching of muscles innervated by the nerve root adjacent to the catheter can be triggered by a typical threshold current of 1.0–9.9 milliamperes. Twitching in the quadriceps indicates lumbar catheter placement. Twitching in the gluteus, hamstring, calf, or foot suggests sacral placement. Analgesic medicine was then delivered. 3 hours later, a 0-10 pain score and loss of cold sensation to ice were recorded. The primary outcome is to identify the efficacy of the EST in determining the epidural catheter's position for labor analgesia in relation to the patient's loss of cold sensation to ice 3 hours later. The secondary outcome was catheter success, defined as self-reported pain score <3 at 3 hours. A two-proportion z-test was used to assess the relationship between activated muscle groups and catheter success.

Results: Primary outcome - Of the 21 patients who completed this study, 19 reported loss of sensation to ice. In all 19, muscle twitching was observed during EST. Secondary outcome - Of the 21 patients who completed the study, 18 experienced twitching in their quadriceps (lumbar plexus group) and 3 experienced twitching in their gluteus, hamstring, calf, or foot (sacral plexus group). In the lumbar plexus group, 16 patients reported a 3-hour pain score <3. In the sacral plexus group, 1 patient reported a 3-hour pain score <3. Using a two-proportion z-test, p=0.0232.

Conclusion: The epidural stimulation test is a valid noninvasive technique to confirm lumbar epidural placement in laboring patients. EST-induced quadricep twitching is associated with better labor analgesia compared to gluteus, hamstring, calf, or foot twitching.

References: [1] Carvalho, B. Failed epidural top-up for cesarean delivery for failure to progress in labor: the case against single-shot spinal anesthesia, Int J Obstet Anesth 2012; 21: 357–9.
[2] Arendt, K., et al. Why epidurals do not always work, Rev Obstet Gynecol 2008; 1(2): 49-55.
[3] Tsui, B., et al. Confirmation of epidural catheter placement using nerve stimulation, Can J Anaesth 1998; 45(7): 640-4.

Early prediction of sub-optimal labor epidural analgesia using electrical stimulation test

Background
A post-dural puncture headache (PDPH) is a common complication following trauma from spinal or epidural procedures. While the gold standard of treatment is an epidural blood patch (EBP), numerous pharmaceuticals have been investigated to prevent and manage symptoms with varying results. In some studies, gabapentin has been shown to decrease the incidence and severity of PDPH and opioid consumption without significant adverse effects.
Case Presentation
A 22-year-old female presented with an intractable headache after a recent lumbar puncture (LP). She was receiving treatment with REPOCH and intrathecal (IT) methotrexate for Burkitt’s Lymphoma and had end-stage renal disease status-post a remote kidney transplant complicated by post-transplant lymphoproliferative disorder. At presentation, her associated symptoms included nausea, vomiting, and severe pain that improved with lying flat, consistent with a PDPH. Initial treatment included fluids, opioids, anti-emetics, and caffeine. However, the patient required hospitalization due to her symptoms for which Anesthesiology and Palliative
Medicine were consulted. Since the patient had future cycles of IT chemotherapy and was a high infectious risk due to her immunocompromised state, an EBP was not recommended. Steroids, acetaminophen, and NSAIDs were contraindicated given her neutropenic fever and renal dysfunction, respectively. Gabapentin 100mg TID was then recommended based on limited evidence. The patient experienced significant symptom relief with gabapentin, decreasing her opioid utilization from over 100 oral morphine equivalents to zero within 24 hours. Gabapentin was prescribed for the patient’s future LP schedule that included three days of prophylactic treatment followed by three days of therapeutic treatment. The patient’s last chemotherapy was completed a few months later without recurrence of her headache.
Discussion
Management of PDPH includes a wide variety of treatment options in the literature with new non-opioid medications undergoing ongoing investigation. Clinicians should consider the use of gabapentin in the treatment and prevention of PDPH for patients who fail standard therapies.

The Use of Gabapentin for Relief of Post-Dural Puncture Headache

Brugada syndrome is characterized by coved-type ST-segment elevations in the precordial leads associated with syncope, life-threatening ventricular tachyarrhythmias and sudden cardiac death. When typical ECG findings are present in the absence of symptoms, it is called Brugada pattern. About 25% of cases are associated with loss-of-function mutation of the cardiac sodium channel SCN5A while others may be triggered by drugs with sodium channel-blocking effects, electrolyte abnormalities, febrile states, or autonomic dysfunction.

A 33-year-old man presented with a 3-day history of intermittent substernal chest pressure. On hospital admission, ECG showed normal sinus rhythm without ST-segment changes and serial cardiac enzymes were normal. Given persistent symptoms and unremarkable recent exercise ECG-stress testing, cardiac CT-angiography was performed which revealed anomalous origin of the right coronary artery (RCA) with approximately 50% luminal narrowing. The patient underwent successful surgical reimplantation of the RCA. Cardiopulmonary bypass was weaned
off and the patient rewarmed from therapeutic hypothermia. Once normothermia was achieved, the patient developed ventricular fibrillation (VF). Following successful resuscitation, ECG revealed ST-segment elevations in V1 and V2 consistent with type 1 Brugada, which completely resolved spontaneously in the subsequent hours and was not reproducible with ajmaline challenge.

It is well known that hyperthermia may trigger Brugada syndrome in predisposed individuals. Studies have shown that mutated sodium channels result in temperature-dependent ionic changes. In febrile states, delayed sodium influx results in heterogeneous depolarization predisposing to VF. On the contrary, severe hypothermia (28.5C) causes sinus bradycardia, QT prolongation, widening of the QRS complex and the pathognomonic Osborn wave. Typical Brugada pattern has been rarely described in hypothermic states. Nonetheless, this pattern has been reproduced in animal models with cooling of the epicardium. Therapeutic hypothermia is targeted in the range of mild hypothermia (32-34C), where VF occurs only rarely, mainly in patients with primary arrhythmic disorders. Tan et al. described a case of transient typical Brugada ECG pattern upon rewarming from therapeutic hypothermia after sudden cardiac death of unknown etiology, with complete resolution with normothermia. These authors proposed that the Brugada pattern was hidden during the hypothermic state. In our patient, however, VF occurred only during the rewarming phase when normothermia was
achieved. We hypothesize that temperature increments, not necessarily hyperthermia, may be associated with increased risk of Brugada syndrome in susceptible patients. Although further research is needed, rewarming from therapeutic hypothermia requires careful monitoring for potentially lethal arrhythmogenic disorders.

A Warming Surprise: Brugada Syndrome After Rewarming from Therapeutic
Hypothermia

Background 
Lactation support in transgender women is increasingly recognized as clinically important yet has limited clinical precedent. While previous case reports describe successful lactation induction their protocols involve domperidone, a galactagogue unavailable for this purpose in the US and recommended against by the US Food and Drug Administration (FDA). We present a case of successful lactation induction in a transgender woman using a protocol not involving galactagogues. 
Case Presentation 
Our patient was a 36-year-old transgender woman, a United States military veteran 
receiving care through the Veterans Health Administration (VHA), who was planning on having a child with her partner and wanted to breastfeed. Her partner, a transgender man, carried and delivered the child and wished to return to testosterone use shortly after delivery. Her primary goals included sufficient milk production to allow bonding, even if not the sole source of infant nutrition. Our multidisciplinary team included a clinical pharmacist with gender-affirming hormone therapy expertise and a lactation specialist with gender-affirming therapy expertise. Our patient was status post orchiectomy with an initial testosterone level of 27 ng/dL, and on a dose of 4mg PO 17-beta estradiol. We began the patient’s lactation induction 98 days prior to her partner’s pregnancy and 377 days prior to her 
partner’s eventual due date. Our protocol involved 1) increased estrogen and 
progesterone to mimic physiologic levels during pregnancy; 2) physical nipple stimulation using a breast pump; and 3) reduced estrogen and progesterone shortly before delivery to mimic physiologic levels after birth. We opted against a galactagogue due to FDA recommendations against domperidone as well as patient concerns of side effects with other galactagogues. Interestingly, our patient’s estradiol levels remained under 200 pg/mL throughout the lactation induction process, even at higher levels of 17-beta estradiol dosing. This is in consonance with other published case-reports on lactation-induction in transwomen. 
Discussion 
Working with a multidisciplinary team including pharmacy and lactation specialists and using a protocol involving (1) initial increase of estradiol and progesterone, (2) nipple stimulation, and (3) eventual reduction of estradiol and progesterone, our patient was able to lactate without the use of galactagogues, allowing her to meet her goal of bonding with her baby. This is the first reported case of successful lactation induction without galactagogues for a transgender woman to our knowledge, and provides an example protocol modeled on physiologic lactation stimuli that other clinicians may adapt with their own patients in similar circumstances.

Inducing lactation in a transgender woman without galactagogues: A case report

Background: Pulmonary hypertension (PH) is a fatal disease associated with pulmonary vascular remodeling that leads to right ventricular (RV) failure and death. While miR-10b-5p exerts pro-proliferative effects in various cancers via inhibition of its targets cell adhesion molecule 1 (CADM1) and apoptotic peptidase activating factor 1 (APAF1), its role in PH is elusive. We hypothesize that PH is associated with upregulation of lung miR10b-5p and downregulation of its targets CADM1 and APAF1. Further, miR10b-5p inhibition may rescue pre-existing PH.

Methods: PH was induced in male rats by monocrotaline (MCT; 60mg/kg sc; n=4; followed for 30-days) or Sugen/Hypoxia (SuHx; SU5416; 20mg/kg sc and 10% O2 hypoxia for 3-wks followed by normoxia for 2-wks; n=3). In vivo inhibition of miR10b-5p was performed from day14-30 after MCT (5 intratracheal injections of antagomir every 3-4 days; 5nM/ injection; n=3). PBS treated MCT rats served as controls (n=5). Rats were followed by echo. RV catheterization was performed terminally, and RV hypertrophy index was calculated. MiRNA microarray was performed to assess miR10b in rat lungs. Lungs were stained to quantify vascular remodeling. RT-PCR was performed to assess gene expression. Human pulmonary artery smooth muscle cells (HPASMCs) were incubated with miR10b mimic for 24h to assess proliferation. Data are mean±SEM. 

Results: MCT and SuHx rats developed severe PH. MiRNA microarray revealed a 3-fold increase in miR10b in MCT rat lungs. PCR validated increased miR10b in MCT and SuHx rat lungs. Further, there was a significant downregulation of miR10b targets CADM1 (MCT 1.64-fold; SuHx 1.48-fold) and APAF1 (MCT 1.23-fold; SuHx 1.21-fold) in lungs. In vivo knockdown of miR10b resulted in rescue of PH in MCT rats (RVSP: 50.7±4.42 in antagomir vs. 95.81±3.70 mmHg in placebo; p<0.005; RV hypertrophy index: 0.52±0.02 in antagomir vs. 0.80±0.07; p<0.05; RVID: diastolic 2.44±0.68 in antagomir vs. 4.55±0.42 mm; p<0.05). PCR demonstrated 30% decrease in lung miR10b and histology revealed reduced pulmonary arteriolar medial wall thickness (32.72±1.12 in antagomir vs. 42.24±3.26% in placebo, p<0.005) in rats treated with antagomir. Finally, miR10b overexpression resulted in HPASMC proliferation in a dose-dependent manner.

Conclusion: Pre-clinical PH is associated with an increase in miR10b-5p expression and decrease in its targets CADM1 and APAF1. miR10b-5p inhibition rescues experimental PH and may serve as a novel therapeutic target.


MicroRNA10b-5p Inhibition as a Novel Therapeutic Strategy for Severe Pulmonary Hypertension

Acute osteomyelitis in the setting of chronic steroid therapy for the treatment of 17-alpha-hydroxylase deficient congenital adrenal hyperplasia

Background 
Alarm fatigue is a significant issue for clinicians due to excessive exposure to alarms, leading to desensitization and decreased trust in their accuracy. Further, not all alarms in intensive care settings warrant action or immediate attention. This can result in inappropriate alarm silencing, posing risks to patient care, especially in emergencies. To address this, we propose redesigning alarms with descriptive and directional auditory and visual cues, aiming to reduce cognitive load, improve event detection, reaction time, and user satisfaction.

Methods
We designed auditory alarms to differentiate between moderate and severe changes in blood pressure, aiming to improve accuracy and response time by enhancing alarm contrast for varying levels of urgency. Additionally, we developed a custom heads-up display (HUD) to address visual overload from uninformative alarms contributing to alarm fatigue. VUMC providers participated in two trials of auditory testing (Original vs Modified alarms) and visual testing (simulated ICU monitor vs HUD display). After each trial, participants provided subjective feedback on comfort and user satisfaction using NASA-TLX surveys.

Results
Given that p=0.045 for percent correctness in Original vs. Modified alarms, modified auditory alarms improved accuracy, but not response time (p=0.640). However, given that p=0.147 for percent correctness and p=0.323 for response time in First vs. Second trials, accuracy and reaction times did not improve as trials progressed, perhaps suggesting a steep learning curve in familiarization with varying alarm sounds. Interestingly, NASA-TLX survey scores revealed lower average ratings on the metrics of effort and frustration, suggesting improved user comfort with use of modified alarms. 

Preliminary visual data showed no significant difference in percent correct identifications (p = 0.560) with use of HUD. Interestingly, use of HUD trended towards worse performance which may be attributed to lack of familiarity with novel HUD interface. Several participants expressed that they had difficulty readjusting their visual focus between the HUD screen and laptop screen in real time, likely contributing to higher physical demand ratings. 

Conclusions
Our data shows that auditory modifications to alarms are more effective in clinical and intensive care settings compared to traditional alarms. This could significantly improve clinician accuracy in detecting emergent events, leading to better patient outcomes. Future research should explore integrating both auditory and visual modifications to assess their combined impact on accuracy, response time, and user experience. Although user experience was not improved with modified alarms and HUD display, there is potential to enhance the HUD's comfort, wearability, and compatibility with existing ICU monitors.

Mitigating ICU Alarm Fatigue in Clinicians by Integrating Visual and Auditory Feedback

Background: In the last 20 years, African Americans and Hispanics/Latinos have been less likely to receive treatment of any analgesia, including opioids as compared to Whites/Caucasians. Surgery and anesthesia are critical healthcare services and are the mainstay treatment for many pathologies, however, postoperative pain is often a significant concern for surgical patients. Poorly controlled acute postoperative pain is associated with diminished function and mobility, delayed recovery, prolonged opioid use, and higher healthcare costs. Although evidence of disparities in the treatment of pain exists, studies on this topic are limited.
Methods: A systematic review and meta- analysis of cohort studies and cross-sectional analysis of studies published in PubMed, Embase, and Scopus in the last 10 years examining disparities in perioperative pain treatment specifically the use of regional anesthesia and opioid use measured in milligrams of morphine equivalents (MME). Articles with sample populations from the United States examining were included, data from Obstetric, Pediatric (<18 years old), and simulation cases were excluded.
Results: The initial search yielded 640 articles, after abstract and full-text screening 5 studies met the inclusion criteria. The types of surgery included in the review were mastectomy, thoracic surgery, and abdominal surgery. The odds of receiving regional anesthesia of minority populations as compared to whites found to be as follows with: Blacks 0.78 [95% CI: 0.73- 0.82]P<0.00001 and I2 =97%, Asian 0.58[95% CI: 0.54-0.63] ]P<0.00001 and I2 =98%, other
Ó 2023 American Medical Association. All rights reserved.
0.85[95% CI: 0.75-0.96] P=0.83 and I2=0%, Native Hawaiian 0.85[95% CI: 0.63-1.14]P=0.28, Native American 0.93[95% CI: 0.71-1.23] P<0.62. Studies had a significant heterogeneity in reporting opioid consumption; thus, meta-analysis was not feasible. However, some studies did show differences in opioid prescription among minority groups showing the need for more standardized research in the area.
Conclusion: Analysis of existing data demonstrates that overall self-identified minority individuals had lower odds of receiving regional anesthesia for pain control as compared to white/Caucasian patients undergoing the same procedures; thus, highlighting a disparity in acute perioperative pain control The sparse number of available studies in the literature focusing on disparities in acute perioperative pain control poses a challenge to accurate evaluation. The high heterogeneity amongst the studies also limits the strength of evidence. In light of the paltry reporting of disparities in peri-operative pain control, more studies are needed to identify the true nature and size of the underlying issue so the root cause may be elicited and corrected in order to improve health equity.

Disparities in Perioperative Pain Control: A Systematic Review and Meta- Analysis

The kappa-opioid receptor (KOR) has been a target of recent interest in the treatment of alcohol use disorder, due to its role in negatively reinforced ethanol drinking, whereby aversive stimuli can promote ethanol intake. The KOR is densely expressed in the nucleus accumbens (NAc) on terminals of afferent neurons from the ventral tegmental area (VTA), where their activation has been found to suppress dopamine release such as is observed during alcohol withdrawal. We have previously found that KOR agonism differs along the rostro-caudal axis of the NAc shell, and that there may be a sex-related difference in baseline levels of ethanol intake. In the present study, we sought to determine if KOR stimulation in the rostral NAc shell could reverse effects of dopamine afferent activation on ethanol drinking. In Experiments 1 and 2, we used Long-Evans rats, as well as female transgenic tyrosine hydroxylase (TH)-Cre rats on a Long-Evans background in Experiment 3, which have a TH promoter directing expression of Cre recombinase in dopamine-containing cells, and we allowed them to drink under an intermittent access model, which establishes binge-like ethanol drinking. After the establishment of stable drinking, we bilaterally infused an excitatory designer receptors exclusively activated by designer drugs (DREADD) virus in the VTA of Experiment 2 groups, and a Cre-dependent excitatory DREADD in the VTA of the Experiment 3 group. After time for transduction, we injected into the NAc shell (1) the DREADD agonist, clozapine-N-oxide (CNO) (Experiments 2-3), (2) the KOR agonist, U50,488H (Experiments 1-3), (3) CNO + U50,488H (Experiments 2-3), and (4) saline vehicle (Experiments 1-3), counterbalanced in a Latin-Square design, and measured subsequent ethanol drinking. Surprisingly, we found that both U50,488H and CNO, independently and combined, enhanced ethanol drinking in high-level drinkers, and that these effects were not additive. Furthermore, the opposite trend was seen in low-level drinkers, suggesting a phenotype-dependent effect. These results suggest that both the DREADD activation and the KOR agonist microinjection have a similar net effect on dopamine release into the NAc shell, and that these effects depended on the phenotype of the drinker. The findings support the use of KOR antagonism as a therapy for alcohol use disorder, despite its potential unconventional effects on the dopamine system, and the overall use of individualized medication that considers an individual’s sex and phenotype.

Effects of Dopamine and Kappa Opioid Receptor Activity in the Rostral Nucleus Accumbens Shell on Ethanol Drinking in Rats

ATPase Inhibitory Factor 1 (IF1) is a nuclear-encoded ATP synthase-interacting mitochondrial protein. IF1 is known to be upregulated during periods of elevated stress, such as during myocardial infarctions or cardiac hypertrophy. Previously conducted lab research has demonstrated that mice with the absence of the protein IF1 were protected against pathological cardiac hypertrophy. To further investigate the extent of such findings, an experiment was designed to investigate the role of the IF1 protein in cardiotoxic conditions induced by Doxorubicin (DOX), a widely used anti-cancer drug. DOX is known to induce cardiotoxicity through the generation of reactive oxygen species, increased levels of lipid peroxidation, and mitochondrial dysfunction. Doxorubicin-induced cardiomyopathy is associated with a low prognosis and can serve to be fatal in certain populations. We hypothesized that mice with the absence of IF1 will demonstrate more preserved cardiac functions in the presence of DOX. 

To test the hypothesis, DOX was intraperitoneally injected into two separate groups of mice: mice for which the IF1 protein was knocked out (IF1-KO) and wildtype mice normally expressing the IF1 protein (IF1-WT). The drug was dissolved in a solvent consisting of dimethyl sulfoxide (DMSO), PEG-300, Tween-80, and distilled water in pre-designated proportions. Injections were performed on three separate days with 6 mg/kg of DOX administered on each injection day. Injections were conducted on Day 0, Day 2, and Day 4. Control mice were injected simply with solvent. Subsequently, transthoracic echocardiograms were performed using a VEVO F2 system at one-week intervals for three weeks ie. Day 7, Day 14, and Day 21. Long-axis M-Mode images were obtained to analyze systolic parameters: ejection fraction, fractional shortening, left ventricular mass, as well as left ventricle anterior and posterior wall thickness. Body mass was also measured initially and after the three-week interval. Findings demonstrated that in the presence of DOX, ejection fraction and fractional shortening, the two parameters of cardiac contraction, significantly decreased in IF1-WT mice; whereas no significant decrease was seen in IF1-KO mice. Furthermore, left ventricular anterior wall thickness was found to be significantly reduced in both IF1-WT and IF1-KO mice, suggesting that DOX may lead to a decrease in heart size. These results demonstrate that the absence of IF1 may provide protection against the cardiotoxic effects of DOX, thus supporting the hypothesis. Further studies could investigate the role of increased doses of DOX on cardiac physiology as well as the effects of increased time intervals through the performance of transthoracic echocardiograms after five to seven weeks. Future experiments using other pathophysiological and biochemical methodologies will gain further insights into the mechanisms of the protective effects of eliminating IF1. Experimental findings may yield new insights into the development of interventions to mitigate adverse effects of this drug in cancer patients under chemotherapy treatments.


Analysis of the Role of ATPase Inhibitory Factor 1 (IF1) in Doxorubicin-Induced Cardiotoxicity

Background:
Unintended perioperative hypothermia, defined as having a core-body temperature less than 36 degrees Celsius, occurs in 78.6 % of patients undergoing general anesthesia. Additionally, it is also seen post-operatively in the SICU as well. Concurrently, peri and postoperative hypothermia is also associated with higher rates of infection, increased recovery time, cardiovascular diseases, perioperative hemorrhage, and impairment of drug metabolism. Therefore, it is crucial to limit the incidence of peri and postoperative hypothermia because it is both adjustable and advantageous for the patient. Doing so limits postoperative complications and future surgical interventions. The research goal was to determine the efficacy of using either a water-circulating device or a forced air warming system maintaining both peri/postoperative normothermia during thoracic and abdominal surgeries.

Methods:
A systematic review of randomized controlled trials and non-randomized studies addressing the efficacy of surgical warming systems was conducted. The impact of a water circulating device and a forced air warming system on maintaining peri and postoperative normothermia during abdominal and thoracic surgical procedures were analyzed.

Results:
The initial search of databases returned a total of 28 publications. Five total randomized controlled studies and non-randomized studies were included and analyzed in this review. There was a statistically significant difference in mean core body temperature in patient’s using the water-circulating device when compared to the forced air warming system during thoracic and abdominal procedures perioperatively in both the randomized controlled studies and non-randomized studies, mean difference of 0.45, p=0.0002, 95% CI [0.21,0.69] and mean difference of 0.47, p=0.001, 95% CI [0.18,0.75], respectively. There was not a statistically significant difference in mean core body temperature in patient’s using the water-circulating device when compared to the forced air warming system during thoracic and abdominal procedures postoperatively in the randomized controlled studies, mean difference of 0.41, p=0.34, 95% CI [-1.08,1.33]. There was a slight difference in the maintenance of normothermia postoperatively in the nonrandomized studies, mean difference of 0.89, p=0.02, 95% CI [0.12,1.65].

Conclusion
The investigated water warming system results in better maintenance of intraoperative normothermia than routine air forced warming applied to the upper and lower body.


Water Circulating Device versus Forced Air Warming System in Prevention of Hypothermia during Thoracic and Abdominal Surgeries: a Meta Analysis

Background:
Annually, over 300 million patients undergo surgery requiring the administration of a combination of anesthetic pharmacologic compounds (APCs). Surgery is associated with significant tissue trauma, triggering a complex inflammatory response that engages the innate and adaptive branches of the immune system. Complications, including end-organ damage, infections, and protracted recovery, arise as pro-inflammatory and immune-suppressive responses tilt out of balance. Accumulating evidence suggests that, in addition to desired anesthetic properties, many APCs have immune-modulatory properties that can positively or negatively impact surgical recovery. However, the effect of APCs on specific innate and
adaptive immune cell functions warrants further exploration to personalize anesthetic choice based on individual patient and surgery needs. We hypothesize that APCs alter critical immune cell responses and effector functions implicated in the human immune response to trauma and injury.

Methods:
We developed a high-throughput multiplex mass-tag barcoding (MCB) assay to screen 16 commonly administered APCs for their capacity to modulate trauma-related immune and adaptive immune responses. These include general and local anesthetics, narcotic and benzodiazepine analgesics, neuromuscular blocking agents, and NSAIDs. We also selected ten additional compounds frequently used in anesthesia settings: antiemetics, diuretics, antidotes, catecholamines, and beta blockers. Using single-cell mass cytometry, we quantify the effect of each APC on 1500 intracellular signaling responses in 25 innate and adaptive immune cell subsets in whole blood samples (500µL) across a range of drug concentrations and stimulation conditions, including lipopolysaccharide (LPS), interferon alpha (IFNa), and a cocktail of interleukins 2, 4, and 6.

Results:
A first MCB screen was completed using flunisolide, a glucocorticoid compound with a known immunosuppressive effect, allowing for assay optimization. This identified marked changes in protein phosphorylation of inflammatory pathways between immune cells exposed and not exposed to flunisolide. These results show that flunisolide inhibited adaptive immune cell subsets to a greater extent than innate immune cell subsets in a cell-type and signaling response-specific manner.

Conclusion:
Having established the MCB experimental framework, the next experiments will systematically evaluate the immune-modulatory properties of the proposed library of APCs. Eventually, the MCB assay could be utilized clinically to determine the immune-modulatory effect of a complex anesthesia regimen – a first step toward personalized anesthesia.

Underline digital video library

Early prediction of sub-optimal labor epidural analgesia using electrical stimulation test

The Use of Gabapentin for Relief of Post-Dural Puncture Headache

A Warming Surprise: Brugada Syndrome After Rewarming from Therapeutic Hypothermia

Inducing lactation in a transgender woman without galactagogues: A case report

MicroRNA10b-5p Inhibition as a Novel Therapeutic Strategy for Severe Pulmonary Hypertension

Acute osteomyelitis in the setting of chronic steroid therapy for the treatment of 17-alpha-hydroxylase deficient congenital adrenal hyperplasia

Mitigating ICU Alarm Fatigue in Clinicians by Integrating Visual and Auditory Feedback

Disparities in Perioperative Pain Control: A Systematic Review and Meta- Analysis

Effects of Dopamine and Kappa Opioid Receptor Activity in the Rostral Nucleus Accumbens Shell on Ethanol Drinking in Rats

Analysis of the Role of ATPase Inhibitory Factor 1 (IF1) in Doxorubicin-Induced Cardiotoxicity

Water Circulating Device versus Forced Air Warming System in Prevention of Hypothermia during Thoracic and Abdominal Surgeries: a Meta Analysis

A High-Throughput Mass Cytometry Assay to Investigate Immune Cell Modulation of Anesthetic Drugs

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